This project will determine the relative contribution of genetic and trauma-related risk factors for Posttraumatic Stress Disorder (PTSD) in a cross-sectional study of a highly traumatized, low socioeconomic status, minority population. Although some level of fear and stress is normal following a traumatic experience, a critical question is why chronic pathological symptoms do not occur in all who experience trauma. Individuals appear to have different vulnerabilities in their traumatic stress response. It is likely that PTSD results from an interaction of predisposing genetic and environmental risks that enhance the likelihood of a pathological stress response and fear memory following severe trauma. However, almost nothing is known of the nature of the genetic contribution(s) to PTSD and how they interact with other risk factors. We will examine 1000 non-psychiatric patients from the General Medical Clinic at Grady Memorial Hospital in Atlanta. Our pilot data suggests that over 80% of this population has suffered significant trauma and approximately 30% have PTSD. We will examine independent factors that contribute to the relative risk for PTSD following trauma: genotype polymorphism, lifetime history of trauma, and peri-traumatic emotional response to the PTSD-related event. Genetic risk factors include polymorphisms that have been described in the development of other stress-related psychiatric disorders, including monoamine related genes (5HTT, DBH, DAT, and COMT), brain-derived neurotrophic factor (BDNF), and genes involved in HPA axis regulation (GR, CRF-R1, FKBP5). Lifetime history of trauma includes childhood trauma and total lifetime trauma. Emotional response to trauma includes subjective severity as well as peri-traumatic dissociation. Covariates to be examined include family psychiatric history, substance abuse / dependence, and comorbid psychiatric diagnoses. The primary dependent variables include presence or absence of PTSD diagnosis and its severity. PTSD is a complex disorder with symptomatic variants. Successful genetic association studies in other complex disorders have relied upon analysis of specific traits, or 'endophenotypes', that comprise separate aspects of the disorder. Therefore, this study will also examine secondary dependent trait variables, or endophenotypes of PTSD:1)intrusive, hyperarousal, and avoidant symptoms;2) physiological markers of HPA dysregulation (cortisol and ACTH at baseline, after dex-suppression and dex-CRH tests);and 3) assessment of baseline and dark-enhanced acoustic startle. By examining identified candidate genes, trauma history, and PTSD diagnosis as well as its component traits, this study will further the understanding of PTSD. Through a greater understanding of the vulnerability factors, both genetic and environmental, that contribute to pathological fear and stress following a trauma, this work will further the development of model systems as well as potentially provide novel intervention, diagnostic, and treatment approaches for this debilitating disorder.